All right. Good morning, everyone. Day three, day three of our Jefferies Healthcare Conference here in New York City. I hope everyone's enjoying it so far. I have the pleasure of hosting the Apogee Management team. I'm gonna hand it off to Michael for some brief introductory remarks, and then we'll get going with one-on-ones. Great. Thank you, and thank you, everyone, for making the time this morning. You know, really excited to share more about the Apogee story. So we're developing potentially best-in-class antibodies, both monotherapies and combinations, leading to the largest markets in I&I. So our lead is focused on atopic derm, COPD, and asthma, also kind of rounding out the indications that we've disclosed. We think that each of our drugs has the potential to be best in class in the largest markets, with our lead in particular, having Phase II data next year, which could show it to be best in class in a $50 billion type of market. All of our antibodies are fully optimized to have both long half-life and, you know, improved backbones, improved solubility. Then we take those monotherapies, and we'll aim to do combinations as well to further break that efficacy ceiling. So really excited to dive in and share more. Awesome. Thanks so much. You know, I wanted to start off not with atopic derm, where I think people definitely understand the beginnings of that story, but actually on your respiratory franchise, where I feel like maybe there's not enough questions on the, you know, that we get from our clients. OX40, right? I feel like this is always a target that's a little forgotten. You know, Sanofi talks about it a lot, but a lot of people are like, "Oh, well, that's just 'cause they're looking at life after Dupixent." But now you have actually many large cap pharma and biotechs going into the OX40 space and looking at that target. What is the benefit of OX40? What does it provide that might allow you to differentiate in respi indications from a labeling perspective? Yeah. So, you know, I'll start, and then I'll hand it off to, Carl, our CMO. So, you know, OX40 ligand, I think, really is, a very, if it were its own biotech, I think there'd be a lot more attention on it. But right, Sanofi, they have, they say it's the thing that they're most excited about. It is their life after Dupixent, you know, full LCM play, six different phase IIs ongoing, in addition to the phase IIIs that they launched in atopic derm. You know, when we look at kind of what's coming with OX40 ligand over the next year, we're gonna see how it works in asthma. They're running a phase IIb, you know, fully powered AER-type study in asthma, and we will see, can it be beneficial across not just Type II inflammation, not just Type I, but all comers? So very similar to what TEZSPIRE did, but they're looking at this all-comer population, and we'll see, can it be that kind of a broad immunomodulatory agent that is probably gonna be interesting as a mono, but we wanna be the first to then combine it. Mm. By combining it with our... the rest of our pipeline, we think that we could, you know, really have first- and best-in-class combos, and we don't think that any competitors will have that portfolio or be willing to do it. In terms of kind of the mechanistic rationale and why we get excited, Carl, you wanna speak to that? Yeah, so, I'd just say that, right, I think the, you know, OX40 space is developing, you know, fairly rapidly right now. So in, the respiratory front, right, both, rocatinlimab, which is Amgen's OX40, as well as amlitelimab, which is Sanofi's OX40L, and we have an OX40L, you know, both doing asthma studies, so excited to see, where they are, where they end up. To Michael's point, right, we have six biologics approved in asthma right now, but five of them require some kind of, targeted, you know, some kind of, Th2 signature or IgE signature, before using them, too. So right, there's still a lot of space open in terms of, broader biologics, for patients that don't necessarily, qualify for, the ones that have high EO counts or other things associated with their use. I think that's where OX40 could be quite, and/or OX40L could be quite interesting here. Just mechanistically, quite broad, right? It hits both Th, or sorry, Type I, Type II, and Type III inflammation. You know, Type I really being interferons and other gamma chain, associated inflammation. Type II, we already have a lot of stuff there in, with both IL-5s as well as, Dupixent in asthma, although it hits, the Th2 pathway as well. And then, finally, with Type III inflammation, Th17 and Th22 hits that as well. So, you know, very exciting that it could have broader potential in asthma than some of the currently available therapies and/or, you know, if we can translate the asthma data to COPD as well, where the heterogeneity of inflammation is much broader than asthma. You know, we know that somewhere between 40%-60% of patients with asthma have a very defined Th2 signature. It's probably more like 30% in COPD, and so, you know, still a lot of patients that could require broader coverage in terms of inflammatory signaling. And then, obviously, we're also excited for OX40L for atopic dermatitis. I know you're trying to steer us away from there, Akash, but I'll bring it back to that too. You know, amlitelimab has shown really nice data there, but it's not quite at the level of IL-13 and IL-4 receptor alpha in terms of monotherapy potential. But where we see the real benefit there is combining our OX40L with our IL-13, so our first and third programs, APG-777 and APG-990, where we can have, you know, atopic derm is very Th2 driven, but it's not the only inflammatory type, and there's subpopulations based on either regional or ethnic background, as well as type of disease, severity of disease, etc., where they have a little less Th2 involvement or more type I and type III inflammatory involvement. And so by combining the really clear driver of IL-13 inhibition in APG-777 with a broader background of APG-990 or OX40L inhibition, we believe we can both target the key driver, IL-13, and inhibit some of this heterogeneity in atopic dermatitis. Mm-hmm. -to really kind of have a best-in-class combination approach and a first-in-class combination approach in atopic dermatitis as well. Yeah, maybe to that point on, on atopic derm, if you think about best in class, when you think about safety and efficacy, you know, the JAK inhibitors would kind of come to mind. If you were to, let's say, call your shot on atopic derm with a combo of an IL-13 OX40, do you think you could have JAK inhibitor-like efficacy with that regimen? Yeah, I think the combination that makes the most sense to get close to JAK-like efficacy is really OX40L plus IL-13, which is the combination we're going after. The reason being, what JAKs do really well is inhibit Type 1, Type 2, and Type 3 inflammation to a very, very specific intent, right? Like, a very potent extent, which, you know, has caused potentially side effects, etc. And by combining the... You know, OX40L has been shown to be extremely safe. IL-13 has been shown to be extremely safe, right? So by combining those two mechanisms, hitting Type 1, Type 2, and Type 3, but getting the depth of response with IL-13 inhibition, I think we can get closer to JAK-like efficacy with that background. I contrast that a little with other combination approaches, whether they be bispecific or otherwise, that people are going after, that they don't really hit that broad type I, type II, type III, inflammatory signaling as well. If you look at J&J's recent- Mm. -purchases, right, they're going after IL-13 and IL-22, right? You kind of miss Type 1 inflammation in that, and you miss Th2 inflammation in that. They're going after IL-4 receptor alpha and IL-31. Those are both Type 2 inflammation, so you're missing the background heterogeneity there. They're going after a lot of different combinations, and I'm not sure what the thesis is, but they're going after IL-13 and TSLP. We know TSLP didn't work well in atopic dermatitis. Placebo-adjusted EASI-15 or EASI-75 rates are, like, less than 10%, right? So when you think about the most rational combo you can do to get to JAK-like efficacy, it's really OX40L and IL-13, the broad inhibition from OX40L and the depth of Th2 inhibition from IL-13. Understood. Maybe same idea in terms of that combination for respi, let's say, in COPD. Any thoughts on— Because I looked at the TSLP data, and, you know, Amgen and AstraZeneca are talking about that 150 eosinophil cutoff. You look at the Dupixent data, it does very well in patients who are under 300 eosinophils. To me, it seems like it was an arbitrary cutoff. Both drugs would have been able to do it. Talk to me about, okay, if you're hitting multiple, you know, type one, type two, when you think about how COPD is traditionally stratified, non-smokers, smokers, on triple therapy or not, what would your label ideally look like in COPD? Would you need a biomarker requirement? Yeah. So I think here, it's we'll share more and more and more about our plans in COPD, especially as we share more about the new target that we added earlier this year. Mm. Right, it does play into combo and respiratory, and, you know, helps us to think about a broader, sort of, population. So I think more to come. We also want to see how the OX40 ligand data looks in asthma, right? I think if that looks compelling in asthma, then we'll, right, have a, a potential combo partner there that could help us to think about a broader label than what, you know, Dupixent, how they design their trials. Okay, understood. Now, in terms of what's needed to be done with the combination, again, I think anyone who's started due diligence on your name or Spyre, you're looking at the FDA draft guidance on novel drug-drug combos. And, you know, there's this A, question of overlapping toxicity, and then there's B, this question of preclinically and then clinically, what you need to do from an enabling side to for the FDA to actually be comfortable with you moving with the combo. You've talked about a combination on the IL-13 and OX40 starting sometime in 2025. What is the symphony of events that need to occur, the data you need to generate in hand for the FDA to be comfortable with that? Yeah. Carl, do you want to speak to that? Yeah, happy to. So, you know, I think as we see it, right, and you referenced the FDA draft guidance, right? Which is, you know, very FDA guidance, which means it tells you nothing and everything at the same time. But, I think we see kind of three components overall to what we need to do there. One is healthy volunteer data for both monotherapies, right? We need to show we can get both monotherapies in the clinic and that they're safe. That goes to kind of proving non-overlapping tox, at least as an initial standpoint. Second is kind of, I'll say, the preclinical reason to believe, right? So what do we need to show to show that there is some either additive or, or synergistic effect, preclinically, whether it be in vitro or, or animal models, right, to just say there's a rationale for this moving forward there. And then the third is kind of preclinically toxicology-wise, both as monotherapies and in combo, to make sure that at least in, in animal species, and here it would be non-human primates, that there's not any, any overlapping tox from that standpoint. So those are, like, the three components we see as as important before we're able to launch combination studies, and then obviously going from starting combination studies to proving to the, you know, agency, ourselves and the agency that it has benefits in patients, et cetera, is, you know, we're gonna need to show in studies at some point in time, right, the contribution of components of each of these. To me, that's not necessarily a starting requirement. That's more of a, you know, a BLA requirement, and when and how we do that, I think, you know, will require not only internal, but agency discussions over time too, 'cause this is- Right. - not something they have seen, a lot overall in development. So, a couple points to expand on that. So number one, you talked about you need healthy volunteer data, but I think, you know, when I talked to your team, especially going into the initial 777 data, there was a sense that you'd be able to hit adequate exposure very quickly in your healthy volunteer studies. So is it as simple as, "Hey, I have to generate healthy volunteer data," or is it, "I need to generate enough data and feel comfortable with our go-forward dose?" And if that's the case, when we think about some of your other healthy volunteer data sets that are coming out, do you share that confidence that, you know, you'd very quickly be able to find adequate exposure? Yeah, I think as we, you know, design our initial studies, right, we're always thinking about how we can move forward as, as rapidly as possible. And, and, you know, thus far for our programs, right, our... We haven't seen any rate-limiting tox in our, our non-human primate studies, meaning that, for all three programs, the, the NOAEL was just the maximum feasible dose or the highest dose tested, right? So that helps enable us to be able to move into, to phase I studies with, you know, drug amounts and exposure levels that are closer to what we think we need to achieve, long term. So, so that's a very helpful phase. Mm. Again, emphasizing, I think, the safety of the three programs we have and the safety of the targets that we've had. I don't think we need to have our go-forward dose, but I think we need to adequately show that we have safety coverage or safety margins, not only from our non-human primate studies, which we've had thus far, but also from healthy volunteer data to, you know, make the regulatory agencies and IRBs comfortable with what we're going forward with in the combos in terms of exposure levels. Understood. Now, I'm gonna maybe go into costs as well, and I'd love, Jane, for you to make a comment. I mean, I think, you know, you have a high-class problem, which is you're going for a lot of different indications. This is traditionally gonna be a large cap pharma type of endeavor. You have over $800 million in cash on hand, but as you think about learning from, let's say, the Dupixent or lebrikizumab development program, you've talked about these integrated phase IIa, phase IIb's. Can you talk about the size of those studies, and then also general, I know maybe you can't comment on the full cost, but per patient cost for some of those trials, why is that integrated phase II-a to be a good idea? How can you be smart from a cost perspective so that, you know, we're not diluting everyone? Yeah, absolutely. Sure. So the phase II-a/b, as you noted, is an integrated design. The II-a portion is about 110 patients, the IIb portion about 360. And then as you look at the phase IIIs, we've not guided on that design yet, but you can, to your point, look at DUPI and LEBRY. Those are two phase III trials for approval of about 400-500 patients each. As we think about per patient cost, you need to think of a range, so about $150,000-$250,000 per patient. The longer the trial, the more sites, the higher end of that range. Shorter trial, fewer sites, the lower end of that range. So as we are looking at being very disciplined on the deployment of that capital, that strong cash position, we're prioritizing triple seven in AD and looking to move that as quickly as possible through clinical trials and a BLA filing. We do have a robust pipeline, but we're gonna be very disciplined and look to see data before we invest heavily in those programs to make sure that we're creating value appropriately and, to your point, not incurring dilution when we shouldn't be. Understood. Now, also, when we think about designing those phase II-as, you know, we were talking about this in the dinner last night. It's always fascinating. You go to these, like, large phase IIIs when you start going into different geographies, and there's a lot of variability sometimes in terms of certain... whether it's, you know, race, whether it's standard of care, you can have very dramatic differences of the same drug. When you think about your phase II-a and designing a study that can really amplify a signal, right? And both for things like atopic dermatitis, but let's also talk about in resp indications, like, you know, we think about - let's think about the Sanofi TSLP IL-13. How do you design a study to limit that type of underlying variability that you see in these populations? Yeah. You know, so, you know, thought a lot about the phase III design, not only from the integrated component, which we believe the phase II-a, phase II-b integrated design can save us kind of years over a traditional path. But also, Akash, what you're talking about, which is: how do we design a study that maximizes our chance of success and our readout here? You know, we believe we have a drug that's, you know, heavily de-risked compared to your normal program at this phase in terms of having an overlapping epitope with lebrikizumab, similar potency, and then obviously the differentiation in the extended half-life. We wanna make sure that that readout is what we all expect. And one of the key pieces is operationalizing the trial correctly. As we think about that, in terms of making sure we decrease, I would say, random variability overall, right? We think about site selection and country selection a lot, and really looking for those sites and countries that have produced the best data overall that have really, you know, potentially a more homogeneous population than if we go broader and wider. So for that study, right, we're looking at U.S., Canada, and Europe as the main enrolling countries. They, you know, have the benefit of having the most experience in terms of AD studies overall, which is really key for them, the sites, to be able to enroll the right patients for us that are likely to benefit from treatment, and, you know, that meet our IE criteria, but truly meet our IE criteria, and there's kind of not a borderline patients being enrolled. So really important for data integrity there overall to be going to countries we know have done well. There's also a hemisphere piece to this, too, right? AD does have some seasonality to it, so keeping it all in the northern hemisphere is also important for that aspect of it. And then, you know, as we see differences in cytokine levels in terms of, you know, geography, this really gives us a more consistent background in terms of what we can expect for our cytokine makeup and, therefore, how much they're likely to respond to, you know, IL-13 directed therapy. So thought a lot about that, making sure that the trial design is very rigorous, but also how we operationalize it maximizes the, you know, readout second half of next year. Understood. I wanted to hit back on actually respiratory. I think this is an important point. I think a lot of... You know, if people say, "Hey, what's the biological risk Apogee is taking?" It's like, okay, IL-13 with lebrikizumab at lower doses didn't necessarily work in asthma, and then they're not taking this in COPD. What's-- you know, why do they feel that? I think... Can you talk about maybe some regulatory or life cycle management considerations that are also driving your decision about taking your IL-4 into COPD instead of the IL-13? Yeah. You know, it's really, it's a reflection of the IRA, right? So, Inflation Reduction Act, when we think about all the different indications where Dupixent or lebrikizumab can exist, COPD is the only one that's really exposed. So when we think about, right, our eventual, you know, triple seven profile, and we think it could be, you know, a $10 billion+ drug, keeping it, you know, fully commercial and then isolating any IRA exposure onto 808 and COPD, is, you know, when we kinda looked at it, the optimal path. And it is just a reflection of, how the regulatory environment, and reimbursement, has evolved. Okay, makes sense. Now, here, I'm sure this is a question you get a lot, like: "Oh, why can't anyone do this?" The answer is, I think they can. I mean, it's, it's in the public domain. The other question I get, and I, I do cover Regeneron, is, Hey, Regeneron obviously is very bullish about Dupixent, IP going out. I think they've talked about 2035+ when you think about their method of use patents. What if Regeneron started to do a YTE mutation? Can you talk about at least your understanding of, A, what the competitive landscape is with other long-acting approaches then, and then, B, you know, what's your feeling on maybe, Sanofi Regeneron potentially going forward with their own YTE IL-4s? Yeah. You know, so there, to your point, all kind of the, you know, discussions that both Regeneron and Sanofi have pointed is, right, IP protection via the roadmap, right, 80-plus patent families that we can see to date going out into the 2035-2040 range. You know, I think Sanofi and Regeneron, they have a tactical collaboration on IL-4 receptor alpha, so, you know, our understanding, but of course, you should ask them, is that they would need to agree to work on a longer-acting Dupixent. Could they design around our IP? Right, our IP's out there, right? People can see that we have, you know, for instance, one of the embodiments, we talked about it, you know, adding just YTE on a Dupi, then spent a lot of time making a much better antibody. We do that for all of our antibodies. So I think that, you know, could they get composition on just Dupi plus YT? You know, there's prior art now, so I think they'd have to, you know, start from the beginning and work to design around. Which, to your point, they, they're great antibody engineers. They could do if they agreed with Sanofi to do it, and Sanofi's been pretty vocal that, right, they're focused on their margins and that they are really investing in amlitelimab as their kind of life cycle management because they fully own it and don't have to share things 50/50 on that. So... Could they do it? Yes. Are all the incentives aligned to do it? I don't know. Understood. Well, let's, I'm sure I'll ask for Jennifer on that and figure that out myself. Maybe stepping back, you do have your R&D Day coming up. For investors, what are the top three things they should be looking forward to there? Yeah. So you know, we'll of course look to provide, you know, likely some version of an update on triple seven. Right, we'll balance that with the, you know, desire to present at medical conferences. We'll also share, you know, by that point, more about the new target that we've added. And then, right, the new target does feed into our combination approach. So we'll share more about why we're excited, and with which combos and in what indications. Okay, understood. Maybe before I let you go, when we think about the undisclosed target, right, you know, I talked to Spyre, and they say, "You know, one of the reasons we really like the combo of the Entyvio kind of IL-23 pitches, we have a lot of long-term safety data." So the question is, do you go with the novel target, where maybe you have differentiated biology, or do you go with the target that's really well understood, especially when you're doing novel drug-drug combos and you have to feel comfortable on tox? How do you think about balancing those two carrots here with the target that you're likely gonna disclose at the R&D Day? Yeah. So, you know, I think that safety is paramount in atopic dermatitis and respiratory. Right, JAKs are a fine example of derms, allergists, they do not want to follow labs long term. They do not want safety baggage. So, we kind of hold safety, you know, as a North Star when we think about our targets just because of how important it is. However, we will have first-in-class combination approaches regardless- Right ... because others don't have the full portfolio that we've been amassing. So we don't have to make a sacrifice, I guess. We get to have, you know, our cake and eat it, too, we think. Understood. It's all about having your cake and eating it too, guys. That's, that's... Just remember that. Good headline. Thanks so much for everyone joining us, and thanks so much for the opportunity. Thanks. Thank you.